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5, 6-ring annulated indole derivatives and use thereof

a technology of indole derivatives and ring annulations, which is applied in the direction of indole-indigos, phosphorous compound active ingredients, drug compositions, etc., can solve the problems of poor treatment effect, poor efficacy of hcv infection approaches, and hcv infection complications, etc., to achieve the effect of improving the safety and efficacy of treatment and improving the safety of treatmen

Active Publication Date: 2010-12-23
MERCK SHARP & DOHME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a group of compounds called 5,6-ring annulated indole derivatives (Formula I) and their pharmaceutically acceptable salts, solvates, esters, and prodrugs. These compounds have various ring structures, including cyclopentyl, cyclopentenyl, 5-membered heterocycloalkyl, 5-membered heteroaryl, and others. The compounds can be optionally substituted with various substituents, such as alkyl, aryl, halo, and others. The invention also provides methods for making these compounds and their use in treating various diseases.

Problems solved by technology

The prognosis for patients suffering from HCV infection remains poor as HCV infection is more difficult to treat than other forms of hepatitis.
Present treatment approaches for HCV infection suffer from poor efficacy and unfavorable side-effects and there is currently a strong effort directed to the discovery of HCV replication inhibitors that are useful for the treatment and prevention of HCV related disorders.
Vaccine development, however, has been hampered by the high degree of viral strain heterogeneity and immune evasion and the lack of protection against reinfection, even with the same inoculum.

Method used

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  • 5, 6-ring annulated indole derivatives and use thereof
  • 5, 6-ring annulated indole derivatives and use thereof
  • 5, 6-ring annulated indole derivatives and use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Compound 3

[0467]

Step A

[0468]

[0469]To a solution of 5-aminoindane (3A) (10 g, 75.1 mmol) in EtOAc (50 mL) was added acetic anhydride (8.4 g) and pyridine (6.5 g). The resulting reaction was allowed to stir at room temperature overnight. Et2O (80 mL) was added to the reaction mixture and and the resulting solution was filtered. The collected solid was washed with Et2O (50 mL), then hexane (50 mL) to provide compound 3B (9.92 g) as a gray solid, which was used without further purification. 1H NMR (400 MHz, CDCl3) 7.44 (s, 1H), 7.22 (bs, 1H), 7.14-7.11 (m, 2H), 2.90-2.83 (m, 4H), 2.16 (s, 3H), 2.10-2.02 (m, 2H).

Step B

[0470]

[0471]Bromine (3.4 mL) was added dropwise to a 4° C. solution of compound 3B (9.92 g) in acetic acid (165 mL) at 4° C. When the addition was complete the reaction mixture was stirred for 1 hour at 4° C. and the reaction mixture was then partitioned between EtOAc and 10% aqueous sodium sulfate and the organic phase was separated, washed with saturated s...

example 2

Preparation of Compound 7

[0484]

[0485]To a solution of freshly made sodium methoxide (prepared by dissolving NaOMe (1.72 g, 75.0 mmol) in methanol (30 mL)) was added dropwise to a solution of ethylazidoacetate (3.35 g, 26 mmol), and compound 7A (2 g, 13.6 mmol) in methanol (10 mL) which had been precooled to −20° C. The reaction mixture was stirred at room temperature for 2 hours, then diluted with EtOAc (200 mL). The organic layer was dried (MgSO4), filtered, concentrated in vacuo and purified using flash column chromatography on silica gel (EtOAc / Hexanes) to provide compound 7B (2.7 g) as a colorless liquid.

Step B

[0486]

[0487]To a solution of compound 7B (250 mg) in xylenes (5 mL) was heated at reflux for 30 minutes, then cooled to room temperature and concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel using CH2Cl2 / Hexanes (0 to 50% CH2Cl2) to provide compound 7C as a colorless solid which was used in next step without purifica...

example 3

Preparation of Compound 11

[0500]

Step A

[0501]

[0502]A solution of 1,3-benzothiazol-5-amine, (11A, Maybridge, 16 g, 107 mmol) in concentrated HCl (180 mL) was cooled to −10° C. and to the cooled solution was added very slowly a solution of sodium nitrite (7.66 g,111 mmol) in water (35 mL). After the addition was complete, the reaction mixture was vigorously stirred at −5° C. to 0° C. for 30 minutes. To the reaction mixture was then added, dropwise, a solution of tin(II) chloride (81.0 g, 359 mmol) in concentrated HCl (60 mL). The internal reaction temperature was maintained at or below −5° C. during the addition. The resulting suspension was stirred at −10° C. for about 90 minutes, during which time the reaction mixture was allowed to warm to room temperature. The resulting precipitates were filtered off and the flask was rinsed with small amount of water. The collected solids were dissolved into water (100 mL), and Na2S.9H2O (39 g) was added. The aqueous layer was adjusted to pH 11 u...

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Abstract

The present invention relates to 5,6-ring annulated indole derivatives of the formula (I), compositions comprising at least one 5,6-ring annulated indole derivatives, and methods of using the 5,6-ring annulated indole derivatives for treating or preventing a viral infection or a virus-related disorder in a patient.

Description

FIELD OF THE INVENTION[0001]The present invention relates to 5,6-ring annulated indole derivatives, compositions comprising at least one 5,6-ring annulated indole derivatives, and methods of using the 5,6-ring annulated indole derivatives for treating or preventing a viral infection or a virus-related disorder in a patient.BACKGROUND OF THE INVENTION[0002]HCV is a (+)-sense single-stranded RNA virus that has been implicated as the major causative agent in non-A, non-B hepatitis (NANBH). NANBH is distinguished from other types of viral-induced liver disease, such as hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis delta virus (HDV), as well as from other forms of liver disease such as alcoholism and primary biliary cirrhosis.[0003]Hepatitis C virus is a member of the hepacivirus genus in the family Flaviviridae. It is the major causative agent of non-A, non-B viral hepatitis and is the major cause of transfusion-associated hepatitis and accounts for a significant proportio...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4439C07D401/04C07D491/048C07D513/04C07D417/14C07D401/14C07D471/04A61K31/444A61K31/4709A61K31/519A61K31/517A61K31/4375A61K31/437A61K38/21A61K31/7088A61K39/00A61K39/395A61P31/12
CPCC07D401/04C07D471/04C07D491/04C07D513/04A61P31/12A61P31/14A61P43/00
Inventor BENNETT, FRANKVENKATRAMAN, SRIKANTHNJOROGE, F. GEORGECHEN, KEVIN X.SHIH, NENG-YANGROSENBLUM, STUART B.KOZLOWSKI, JOSEPH A.
Owner MERCK SHARP & DOHME CORP
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